Noninvasive, nuclear imaging techniques can be used to obtain basic and diagnostic information about the physiology and biochemistry of a variety of living subjects including experimental animals, normal humans and patients. These techniques rely on the use of sophisticated imaging instrumentation which is capable of detecting radiation emitted from radiotracers administered to such living subjects. The information obtained can be reconstructed to provide planar and tomographic images which reveal distribution of the radiotracer as a function of time. Use of appropriately designed radiotracers can result in images which contain information on the structure, function and most importantly, the physiology and biochemistry of the subject. Much of this information cannot be obtained by other means. The radiotracers used in these studies are designed to have defined behaviors in vivo which permit the determination of specific information concerning the physiology or biochemistry of the subject or the effects that various diseases or drugs have on the physiology or biochemistry of the subject. Currently, radiotracers are available for obtaining useful information concerning such things as cardiac function, myocardial blood flow, lung perfusion, liver function, brain blood flow, regional brain glucose and oxygen metabolism.
Compounds can be labeled with either positron or gamma emitting radionuclides. For imaging, the most commonly used positron emitting (ET) radionuclides are 11C, 18F, 15O and 13N, all of which are accelerator produced, and have half-lives of 20, 110, 2 and 10 min. respectively. Since the half-lives of these radionuclides are so short, it is only feasible to use them at institutions which have an accelerator on site for their production, thus limiting their use. Given the recent increase in the number of cyclotrons, the positron emitting radionuclide, 18F, is now widely available so that 18F labeled radiotracers are now available to most hospitals in the U.S. and much of the rest of the world. Several gamma-emitting radiotracers are available which can be used by essentially any hospital in the U.S. and in most hospitals worldwide. The most widely used of these are 99mTc, 201Tl and 123I.
In the past two decades, one of the most active areas of nuclear medicine research has been the development of receptor imaging radiotracers. These tracers bind with high affinity and specificity to selective hormone receptors and neuroreceptors. Successful examples include radiotracers for imaging the following receptor systems: estrogen, muscarinic, dopamine D1 and D2, and opiate.
Neuropeptide Y (NPY) is a 36 amino acid peptide that is a member of the pancreatic polypeptide family, which also includes pancreatic polypeptide (PP) and peptide YY (PYY). NPY is located throughout the central and peripheral nervous systems and affects a diverse range of biological functions, including central endocrine secretion, vascular and smooth muscle activity, appetite, memory, anxiety, blood pressure regulation and reproduction. See, e.g., Karla, et al., Phys. & Behavior 50, 5 (1991).
NPY receptors are members of the G protein-coupled receptor superfamily. At present, NPY is known to bind to at least five receptors: Y1, Y2, Y3, Y4 and Y5. NPY Y5 agonists and antagonists are being developed for the treatment of physiological disorders associated with an imbalance of NPY Y5, i.e., as a treatment for obesity, diabetes, anorexia and bulimia.
PET (Positron Emission Tomography) radiotracers and imaging technology may provide a powerful method for clinical evaluation and dose selection of neuropeptide Y Y5 receptor antagonists. Using a fluorine-18 or carbon-11 labeled radiotracer that provides a neuropeptide Y Y5 receptor-specific image in the brain and other tissues, the dose required to saturate neuropeptide Y Y5 receptors can be determined by the blockade of the PET radiotracer image in humans. The rationale for this approach is as follows: efficacy of a neuropeptide Y Y5 receptor antagonist is a consequence of the extent of receptor inhibition, which in turn is a function of the degree of drug-receptor occupancy.
It is, therefore, an object of this invention to develop radiolabeled neuropeptide Y Y5 receptor antagonists that would be useful not only in traditional exploratory and diagnostic imaging applications, but would also be useful in assays, both in vitro and in vivo, for labeling the neuropeptide Y Y5 receptor and for competing with unlabeled neuropeptide Y Y5 receptor antagonists and agonists. It is a further object of this invention to develop novel assays which comprise such radiolabeled compounds.